Bone undergoes continuous remodeling through interactive cycles of bone formation and resorption (bone turnover). Approximately 10% of the bone mass is removed and replaced in an average adult over the course of one year. Osteoclasts and osteoblasts, the major differentiated cells of bone, mediate the remodeling process. Typically, bone resorption is a rapid process that is mediated by osteoclasts, which are cells formed by mononuclear phagocytic precursor cells located at bone remodeling sites. The bone resorption process is followed by the appearance of osteoblasts (bone forming cells), which form bone slowly to replace the lost bone. The fact that completion of this process normally leads to balanced replacement and renewal of bone indicates that the molecular signals and events that influence bone remodeling are tightly controlled.
The mechanism of bone loss is not understood, but in general, bone loss associated disorders arise from an imbalance in the formation of new healthy bone and the resorption of old bone, skewed toward a net loss of bone tissue. This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of the femoral bones and bones in the forearm and vertebrae predominantly. These fractures, in turn, lead to an increase to general morbidity, a marked loss of stature and mobility, and in many cases, an increase in mortality resulting from complications.
Several bone growth disorders are known that cause an imbalance in the bone remodeling cycle. Chief among these are metabolic bone diseases, such as osteoporosis, osteomalacia/rickets, chronic renal failure and hyperparathyroidism, which result in abnormal or excessive loss of bone mass (osteopenia), osteogenesis, osteopetrosis, and Paget's disease. Further, bone loss and a decrease in bone mineralization is often associated with therapies used to treat non-bone associated conditions such as HIV/AIDS, autoimmune disease, epilepsy, and juvenile rheumatoid arthritis, increasing the chances of bone fracture in the recipient.
Improvements in existing therapies and development of new treatments are needed to combat bone loss and promote bone growth. For instance, in the common bone ailment osteoporosis, skeletal mineral losses are in the range of 50% below peak bone mass, which occurs at approximately age 30. Seen from the perspective of correcting the deficit in bone mineral, complete reversal of this 50% loss would require a 100% increase in bone mass. Thus, seen from this perspective, the 2-8% increases in bone mineral density resulting from anti-resorptive therapy may be clinically significant and beneficial, but leaves a lot of room for improvement. Since the use of anti-resorptives to prevent bone loss does not result in new bone production, the ultimate effectiveness of anti-resorptives in quantitative terms is limited. These considerations emphasize the need for the development of pharmaceutical mechanisms to produce new bone.